There is a great need for new therapies active in the treatment of viral diseases. Whereas there has been great progress in developing a variety of therapies for the treatment of bacterial infections, there are few viable therapies for the treatment of viruses. Zidovudine is the primary approved treatment for human immunodeficiency virus. Ganciclovir, acyclovir and foscarnet are currently utilized for the treatment of herpesvirus infections. However, these therapies can have substantial side effects based on their deleterious effects on host cell DNA replication or effect of a limited number of viral infections. In addition, viruses are known to develop resistance to therapies which causes a progressive decline in efficacy [Ljungman et al., J. Infect. Dis., 162, 244 (1990) and Gately et al, J. Infect. Dis., 161, 711 (1990)].
Viruses are classified into broad categories based on whether they incorporate RNA or DNA. Important virus families classified of RNA type include orthomyxoviridae, paramyxoviridae, picornaviridae, rhabdoviridae, coronaviridae, togaviridae, bunyaviridae, arenaviridae and retroviridae. Important virus families classified of DNA type include adenoviridae, poxviridae, papovaviridae and herpesviridae.
Herpesviridae is a family of DNA viruses which include herpes simplex virus type-1 (HSV-1), herpes simplex virus type-2 (HSV-2), cytomegalovirus (CMV), varicella-zoster virus (VZV), Epstein-Barr virus, human herpesvirus-6 (HHV6), human herpesvirus-7 (HHV7), human herpesvirus-8 (HHV8), pseudorabies and rhinotracheitis, among others.
It is known that herpesviruses express their genetic content by directing the synthesis of a number of proteins encoded by the herpesvirus DNA in the host cell. One of the important virus encoded proteins is made as a precursor consisting of an amino terminal-located protease and carboxyl terminal-located assembly protein. This precursor is proteolytically processed in an autocatalytic manner at a specific amino acid sequence known as the "release" site yielding separate protease and assembly protein. The assembly protein is cleaved further by the protease at another specific amino acid sequence known as the "maturation" cleavage site. Recently, EP No. 514,830, published Nov. 25, 1992, describes a virus-specific serine protease which has a role in herpesvirus replication. Additionally, Lui and Roizman [J. Virol, 65, 5149 (1991)] describe the sequence and activity of a protease and the associated assembly protein encoded by U.sub.L 26 of HSV-1. A. R. Welch et al. [Proc. Natl. Acad. Sci. USA, 88, 10792 (1991) and WO93/01291, published Jan. 21, 1993] describe the related protease (also known as assemblin) and assembly protein encoded by U.sub.L 80 of CMV. An approach currently being investigated for potential use in the treatment of herpesvirus infections is the development of inhibitors of herpesvirus proteases.
4H-3,1-Benzoxazinones have been described in the literature as having serine protease activity, among others. While compounds of this type have been reported to have serine protease inhibitory activity, none have been reported to inhibit viral assemblin protease. For example Teshima et al. [J. Biol. Chem., 257, 5085-5091 (1982)] describe various 2-alkyl-4H-3,1-benzoxazin-4-ones as enzyme inhibitors. Moorman and Abeles [J. Amer. Chem. Soc., 104, 6785-6786 (1982)] describe 4H-3,1-benzoxazin-2,4-dione as having some enzyme inhibitory activity. R. Stein, et al. [Biochemistry, 26, 4126-4130, (1987)] describe 2-alkyl-4H-benzoxazin-4-ones, with further substitution at the 5, 6 and 7 positions, as inhibiting the elastase enzyme. WO publication 92/18488 (published Oct. 29, 1992) describes 2-alkyl-4H-3,1-benzoxazin-4-ones with substitution at the 5 and 7 positions as selective inhibitors of elastase. European Application 206,323 (published Dec. 30, 1985) describes 2-alkoxy-, 2-aryloxy- and 2-aralkoxy-4H-3,1-benzoxazin-4-ones, having substitution at the 5, 6, 7, and 8 positions, as enzyme inhibitors. U.S. Pat. No. 4,745,116, to A. Kranz et al. claims 2-alkoxy, 2-aryloxy- and 2-aralkoxy-4H-3,1-benzoxazin-4-ones, having further substitution at the 5, 7 and 8 positions, as enzyme inhibitors.
2-Amino-4H-3,1-benzoxazinones have been described. A. Krantz et al. [J. Med. Chem., 33, 464-479 (1990)] describe 4H-3,1-benzoxazin-4-ones substituted with alkyl, alkylamino, alkoxy and alkylthio substituents at the 2-position, and with further substitution at the 5, 6 and 7 positions, as elastase inhibitors. Uejima, et al. [J. Pharm. Exp. Ther., 265, 516-522 (1993)] describe 2-alkylamino-5-methyl-7-acylamino-4H-3.1-benzoxazin-4-ones as highly selective elastase inhibitors with significant plasma stability. U.S. Pat. No. 4,657,893, to A. Krantz et al, describes 2-alkylamino- and 2-alkylurido-4H-3,1-benzoxazin-4-ones having further substitution at the 5, 7 and 8 positions, as enzyme inhibitors.
F. L. M. Alvarez [An. Quim., 79, 115-17 (1983)] describes the preparation of 2-sulfonylamino-4H-3,1-benzoxazinones. J. G. Tercero et al. [An. Quim., 83, 247-50 (1987)] describe the preparation of 2-arylsulfonylamino-4H-3,1-benzoxazinones.
I. Butula et al. [Croat. Chem. Acta, 54, 105-8 (1981)] describe the synthesis of 2-alkylamino-4H-3,1-benzoxazinones. H. Ulrich et al. [J. Org Chem., 32, 4052-53 (1967)] describe the synthesis of 2-alkylamino-4H-3,1-benzoxazinones. E. Papadopoulos [J. Heterocyclic. Chem., 21, 1411-14 (1984)] describes the use of 2-haloalkylamino-4H-3,1-benzoxazin-4-one as a starting material for the synthesis of phenylureas. European Patent Application 466,944 (published Jan. 22, 1992) describes 2-alkylamino-7-acylamino-5-alkyl-4H-benzoxazin-4-ones as selective enzyme inhibitors of elastase.
M. Badawy et al. [J. Heterocyclic. Chem., 21, 1403-4 (1984)] describe the use of N-phenyl-2-amino-4H-3,1-benzoxazin-4-one as a starting material for the synthesis of quinazolines. R. Khan and R. Rastogi [J. Chem. Research(S), 342-43 (1992)] describe the synthesis of 2-[5-aryl-1,3,4-oxadiazol-2-yl]amino-4H-3,1-benzoxazin-4-ones.
4H-3,1-Benzoxazin-4-ones have not previously been described as selective assemblin protease inhibitors or for the treatment and/or prophylaxis of viral infection.